The bisphosponates, which are salts of bisphosphonic acids, are an important class of medicaments useful in the treatment of bone disorders such as Paget's disease and osteoporosis. The sodium salt of risedronic acid, sodium salt of pamidronic acid, sodium salt of alendronic acid are the examples of pharmaceutically useful bisphosphonates.
The bisphosphonates are derived from the corresponding bisphosphonic acids. Several methods have been reported for preparing 1-hydroxy-1,1-bisphosphonic acids. The syntheses are based on reacting a carboxylic acid with a mixture of phosphorous acid and one of the following phosphorous halides: phosphorous trichloride (PCl3), phosphorous oxychloride (POCl3), phosphorous pentachloride (PCl5), phosphorous tribromide (PBr3), phosphorous oxybromide (POBr3) or phosphorous pentabromide (PBr5), then quenching the reaction mixture with water or a nonoxidizing aqueous acid, followed by heating to hydrolyze the phosphorous intermediates to the final product.
The preparation of 3-amino-1-hydroxypropane-1,1-diphosphonic acid by reaction of beta.-alanine with a mixture of phosphorous trichloride and phosphorous acid in the presence or absence of an organic diluent is known from the German Patent Specification No. 21 30 794. However, yellow-red by-products in the form of amorphous phosphorus-oxygen compounds of unknown structure are formed in this reaction and their separation, particularly in the presence of chlorobenzene, is very costly. Another factor to be considered in the large scale preparations is the dangerously high flammability of these phosphorus compounds
In U.S. Pat. No. 4,407,761 the preparation of 4-amino-1-hydroxybutylidene-1,1-biphosphonic acid besides other bisphosphonic acids are described. When using this procedure, a semisolid sticky non-stirrable mass develops which prevents smooth heat transfer. The described process might be suitable for-laboratory preparations, however for industrial production it is not acceptable.
In U.S. Pat. No. 4,705,651 a similar procedure is followed with different molar ratios and although some improvements were achieved, it is still unsuitable for industrial scale up.
U.S. Pat. Nos. 4,922,007, 5,019,651 and J. Org. Chem. 1995, 60, 8310-8312 reported that the solidification problem has been solved by using methanesulfonic acid to solubilize the reaction components and keep them fluid throughout, by the use of methanesulfonic acid the fluidity problems were solved however another serious safety problem surfaced. A reaction between methanesulfonic acid and phosphorus trichloride is exothermic and at certain point becomes uncontrollable,
U.S. Pat. No. 5,908,959 also describes the preparation of 4-amino-1-hydroxybutylidene-1,1-biphosphonic acid or salts.—thereof. The reaction is carried out in poly(alkylene glycol) as a diluent, which solubilizes the reaction components, however still when the reaction mixture is decomposed with water, an agitation problem occurs. The viscous reaction mixture must be transferred into the water. To facilitate this, viscosity problem is solved by the addition of toluene. When using toluene, a safety problem arises and also an additional separation step is needed.
The present invention solves the problems by allowing the reaction to remain stirrable using anisole as solvent, and making commerical manufacturing possible thus allowing complete conversion of the carboxylic acid providing excellent yields and purity of the formula (I).